The proposed work deals with two major research areas. The first of these is the validation of a new hypothesis on tolerance and dependence to ET using a new animal model. It states that acute and chronic tolerance are distinct phenomena with different neurochemical mechanisms and time courses of development and decay. Chronic tolerance and dependence are stated to have the same underlying mechanism and a similar time course of development and decay. Our animal model uses male rats with gastric catheters and consists of 3-4 daily automated intragastric infusions of ET. We will also evaluate several measures for quantitating tolerance and withdrawal (heart rate, neuromuscular transmission, tremor, swim performance, startle response and body temperature). The other aspect of our work deals with the stress/ET interaction. We will use rats with different brain lesions to determine the neuroanatomical sustrates for ET's action, and whether these brain areas also mediate the protective effects of low doses of ET in stressed animals, as shown by us before. Rats with various lesions of the limbic system will be evaluated with respect to (1) changes in plasma CS and NEFA after high or low doses of ET, and (2) their response to ET when they are also stressed. We will also examine regional levels and turnover of brain noanoamines in stressed ET- and saline-treated rats as well as in non-stressed ET- and saline-treated rats to gain information on the neurochemical mechanisms mediating the interaction of ET and stress. A new direction is the interaction of ET and stress on the heart. After establishing optimal parameters for obtaining stress-induced myocardial damage, we will use histological techniques and the cardiac release of creatine kinase-MB isozyne to quantitatively assess stress-induced damage and the effect of small and large doses of ET. We will also determine the levels and turnover of catecholamines in hearts of stressed and control rats. Finally, we shall test a new hypothesis for the protective and potentiating action of ET on hearts of stressed rats, namely, the effect of ET on cardiac lipases. Our work will provide a basis for studies aimed at elucidating the mechanisms for tolerance and dependence on ET and may alter the approach to treatment and prevention of alcohol abuse and alcoholism in man. Also, besides establishing the neuroanatomical and neurochemical substrates for the interaction of ET and stress in the brain, our work is relevant for the understanding of the consequences of social and abusive ingestion of ET in stressed and nonstressed subjects especially as it relates to the heart.